An abdominal aortic aneurysm (AAA) is a cardiovascular disease with high lethality. It refers to a permanent expansion of an abdominal aortic wall, and if the expansion of the wall is greater than 50% of diameter of adjacent site, or diameter thereof exceeds 3 cm, it can be considered to suffer from an abdominal aortic aneurysm (Johnston K W, Rutherford R B, Tilson M D, Shah D M, Hollier L, Stanley J C. Suggested standards for reporting on Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg. 1991; 13(3):452-458). Once the aneurysmal aorta ruptures, the patient will die from massive blood loss, therefore, an abdominal aortic aneurysm is also called as “the time bomb in the human body”. This disease usually happens in older people, especially in male. The incidence gradually rises with age, and can be up to 8-10%, and the fatality rate reaches to 50%-80%. In USA, the death caused by rapture of an abdominal aortic aneurysm ranks fifteenth in all causes of death and tenth in causes of death of adult male diseases. While in PRC, in the recent 30 years, the incidence thereof rapidly rises by 3 times. However, the pathogenesis and risk factors about this disease are not very clear up to now, therefore, there is no effective method for early prevention, early warning, and drug prevention and treatment. Since DuBost firstly successfully implemented abdominal aortic aneurysm resection and artificial vascular graft at 1951 (DuBost C, Allary M, Oeconomos N. Resection of an aneurysm of the abdominal aorta: reestablishment of the continuity by a preserved human arterial graft, with result after five months. AMA Arch Surg. 1952 March; 64(3):405-8), with the continuous development and improvement of technologies, an endovascular repair has been widely accepted and used worldwidely, and becomes a most commonly used method for treating an abdominal aortic aneurysm at present. However, there are many disadvantages in the surgery, such as high-risk, expensive, not a permanent cure, and difficult to popularize. And as for the patient having a small abdominal aortic aneurysm, that is, when the aneurysmal aorta diameter is less than 5.5 cm, the risk of rupture may be less than the risk of surgery. However, there is no effective drug which can prevent and treat an abdominal aortic aneurysm at present, therefore, exploring a prevention and treatment method for the treatment of abdominal aortic aneurysms now has become a focus and hotspot for cardiovascular research.
A research shows that the pathogenesis of an abdominal aortic aneurysm is mainly due to rise in reactive oxygen species (ROS) of vascular walls, increase in infiltration of inflammatory cells and release of inflammatory cytokines, rise in activities of matrix metalloproteinases (NMP), causing inflammatory response of vascular walls and significant increase of matrix degradation, thereby to result in the onset of abdominal aortic aneurysms (Daugherty A, Cassis L A. Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2004 March; 24(3):429-34). This suggests if drugs for inhibiting vascular inflammatory response or reducing matrix degradation are used, onset and development of abdominal aortic aneurysms may be alleviated or treated. At present, there lacks specific drug treatment schemes supported by large-scale clinical randomized control studies. However, there once are small-scale clinical trials for some drugs for treating abdominal aortic aneurysms, such as statins (Schouten D et al. Statins are Associated with a Reduced Infrarenal Abdominal Aortic Aneurysm Growth. Eur J Vasc Endovasc Surg. 2006 32, 21-26.), macrolide antibiotics (Vammen S et al. Randomized double-blind controlled trial of roxithromycin for prevention of abdominal aortic aneurysm expansion. Br J Surg 2001 88(8):1066-1072), adrenergic receptor blockers (Gregory R et al. Abdominal aortic aneurysm expansion rate: Effect of size and beta-adrenergic blockade. J Vasc Surg.1994 April; 19(4):727-31), and doxycycline (Mosorin M et al. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J Vasc Surg 2001 34(4):606-610), etc., and they all have a certain therapeutic effect on the patients having abdominal aortic aneurysms. In addition, an inhibitor of prostaglandin synthetase (Walton L J et al. Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation.1999 100(1):48-54) and an anti-inflammatory drug, indomethacin, (Holmes D R et al. Indomethacin prevents elastase-induced abdominal aortic aneurysms in the rat. J Surg Res. 1996 June; 63(1):305-9.) also have a certain effect in animal models in which abdominal aortic aneurysms are induced. Most of these drugs are indicated to reduce the inflammatory response of blood vessels, or inhibit the activities of metalloproteinases, thereby to function. However, the above drugs all lack evidences of large-scale randomized control clinical study supporting effectiveness thereof. When applied to clinical trials, some drugs, such as doxycycline, also produce frequent side effects (Baxter B T et al. Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study. J Vasc Surg. 2002 July; 36(1):1-12). Therefore, it will have enormous clinical application value to develop a new drug possessing good prevention and treatment effects and a few side effects for treating abdominal aortic aneurysms.
Naringenin is a natural flavonoids compound, which are highly expressed flavonoids in citrus plants such as grapefruit, shaddock peel, orange peel, and potato peel, and in traditional Chinese medicine, such as Huyou peel, phellinus igniarius, and Ilex centrochinensis. In animal experiments, it has been reported that naringenin can reduce blood fat, and reduce the levels of cholesterol, triglycerides, and low density lipoprotein (LDL-C) in serum, thereby to reduce onset and development of atherosclerosis (Mulvihill E, Assini J, Sutherland B, DiMattia A, Khami M, Koppes J, Sawyez C, Whitman S, Huff M. in High-Fat-Fed Low-Density Lipoprotein Receptor-Null Mice Naringenin Decreases Progression of Atherosclerosis by Improving Dyslipidemia. Arterioscler Thromb Vasc Biol 2010, 30:742-748). It also can regulate immune function and inhibit tumor growth (Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X, Zhang Y, Zhang C, Liang W. Naringenin Decreases Invasiveness and Metastasis by Inhibiting TGF-β-Induced Epithelial to Mesenchymal Transition in Pancreatic Cancer Cells. PLoS ONE 2012; 7(12).). In addition, naringenin also can treat insulin resistance and Type II diabetes (Mulvihill E E, Allister E M, Sutherland B G, Telford D E, Sawyez C G, Edwards J Y, Markle J M, Hegele R A, Huff M W. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes. 2009; 58(10):2198-210), as well as hepatopathy (Morcos P N, Brennan B, Smith P F. A grapefruit a day for patients infected with hepatitis C Hepatology. 2008 June; 47(6):2141-2) in animal models. However, there are no relevant reports about use of naringenin for prevention and treatment of the onset of abdominal aortic aneurysms.